Mollugin Derivatives as Anti-Inflammatory Agents: Design, Synthesis, and NF-κB Inhibition.

Nuclear factor κB (NF-κB) is a key inducible transcription factor that controls a large number of genes involved in inflammatory and immune processes. The entire inflammation-mediated process uses NF-κB as a hub, and inflammatory gene transcription and expression can be decreased by blocking the NF-κB signaling pathway, thereby reducing inflammatory damage. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation.

Design, Synthesis, and Hypoxia-Inducible Factor-1α Inhibitory Activity Evaluation of Panaxadiol Derivatives Containing a Thiazole Moiety.

The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for cancer. Thiazole derivatives have been reported to have diverse biological activities, especially in terms of anti-tumor.

A Comprehensive Review of Traditional Medicinal Uses, Geographical Distribution, Botanical Characterization, Phytochemistry, and Pharmacology of Kitag.

Kitag. () holds significant medicinal value among the genus. It has traditionally been employed in ethnomedicine to address a wide range of conditions, including wind-cold-dampness arthralgia; rheumatic pain in the waist and lower extremities; lumbar muscular strain; injuries resulting from falls, fractures, contusions, and strains; headache; toothache; and abscesses.

Synthesis and biological evaluation of panaxadiol ester derivatives possessing pyrazole and pyrrole moiety as HIF-1α inibitors.

Hypoxia-inducing factor-1α (HIF-1α) is overexpressed in variety of tumor patients and plays an important role in the regulation of hypoxia response in tumor cells. Therefore, its inhibitors have become one of the targets for the treatment of a variety of cancers. Two series of panaxadiol (PD) ester derivatives containing pyrazole (18a-j) and pyrrole (19a-n) moiety were synthesized and their HIF-1α inhibitory activities were evaluated.

Phytochemical Analysis, Antioxidant and Enzyme-Inhibitory Activities, and Multivariate Analysis of Insect Gall Extracts of Nakai.

Nakai (PK) is an evergreen tree. It plays an important role in landscaping and road greening. Insect galls of PK are formed by parasitism of the adelgid .

Development of fluorine-substituted NH-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors: Boosting the safety and metabolic stability.

Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1 (EC = 1.0 nmol/L), but the poor metabolic stability in human liver microsomes (  = 14.6 min) and insufficient selectivity (SI = 2059) with high cytotoxicity (CC = 2.

Synthesis and Evaluation of NF-κB Inhibitory Activity of Mollugin Derivatives.

(1) Background: Nuclear factor κB (NF-κB) is an important transcriptional regulator that regulates the inflammatory pathway and plays a key role in cellular inflammatory and immune responses. The presence of a high concentration of NF-κB is positively correlated with the severity of inflammation. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation; (2) Methods: we designed and synthesized 23 mollugin derivatives and evaluated their inhibitory activity against NF-κB transcription; (3) Results: Compound exhibited the most promising inhibitory activity (IC = 3.

Design, Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives of Panaxadiol.

Based on the well-known cytotoxicity of indole compounds, we used the 'Fisher indole synthesis' method to introduce appropriately substituted indole rings into panaxadiol (PD), generating eighteen novel Panaxadiol indole derivatives. Six human cancer cell lines (A549, HepG-2, HCT-116, SGC-7901, MDA-MB-231, PC-3 cells) and one normal ovarian cell lines (IOSE144) were designed to evaluate the anti-proliferative activity of the PD derivatives. The results showed that the majority of PD derivatives showed enhanced anti-proliferative activity, when compared with PD, with P-Methylindolo-PD exhibiting the highest cytotoxicity.

Discovery of novel biphenyl-substituted pyridone derivatives as potent non-nucleoside reverse transcriptase inhibitors with promising oral bioavailability.

Adding to past success in developing non-nucleoside reverse transcriptase inhibitors (NNRTIs), we report herein our efforts to optimize an FDA-approved NNRTI, doravirine, into a series of novel biphenyl-substituted pyridone derivatives. A strategy focused on harnessing the X-ray crystal structure of doravirine, coupled with computer simulations, to guide the design of conformationally constrained analogs led to the discovery of ZLM-66, which provided comparable inhibitory potency to doravirine against wild-type HIV-1 (EC = 13 nM) and various single/double mutant strains. ZLM-66 possessed acceptable cytotoxicity and selectivity index.

Design of the naphthyl-diarylpyrimidines as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) via structure-based extension into the entrance channel.

A series of novel naphthyl-diarylpyrimidine (DAPY) derivatives were designed and synthesized to explore the entrance channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating different flexible side chains at the C-6 position. The biological evaluation results showed that all analogues possessed promising HIV-1 inhibitory activity at the nanomolar concentration range. Three compounds (7, 9 and 39) displayed excellent potency against WT HIV-1 strain with EC values ranging from 5 to 10 nM and high selectivity indexes (SI = 3504, 30488 and 22846, respectively), which were higher than for nevirapine and comparable to the values for etravirine.

Synthesis and Evaluation of Chiral Rhodanine Derivatives Bearing Quinoxalinyl Imidazole Moiety as ALK5 Inhibitors.

Background: TGF-β signaling pathway inhibition is considered an effective way to prevent the development of several diseases. In the design and synthesis of TGF-β inhibitors, a rhodanine compound containing a quinoxalinyl imidazole moiety was found to have strong antimicrobial activity.

Objective: The purpose of this work was to investigate the antimicrobial activity of other chiral rhodanine TGF-β inhibitors synthesized.

Synthesis and Antimicrobial Activity Evaluation of Imidazole-Fused Imidazo[2,1-b][1,3,4]thiadiazole Analogues.

Three series of new imidazole-fused imidazo[2,1-b][1,3,4]thiadiazole analogues (compounds 20 a-g, 21 a-g, and 22 a-g) have been synthesized, and their antibacterial and antifungal activities have been evaluated. All the target compounds showed strong antifungal activity and high selectivity for the test fungus Candida albicans over Gram-positive and -negative bacteria. N-((4-(2-Cyclopropyl-6-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl)methyl)aniline (21 a) showed the highest activity against C.

Synthesis and evaluation of the epithelial-to- mesenchymal inhibitory activity of indazole-derived imidazoles as dual ALK5/p38α MAP inhibitors.

Drugs of targeting both activin receptor-like kinase 5 (ALK5) and p38α have therapeutic advantages, making them attractive treatment options for tumors. Two series of 4-(1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazoles 13a-g and 4-(1-methyl-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazoles 20a-g were synthesized and evaluated for ALK5 and p38α mitogen-activated protein kinase inhibitory activity. The most potent compound, 13c (J-1090), inhibited ALK5- and p38α-mediated phosphorylation with half-maximal inhibitor concentrations of 0.

The novel ginsenoside AD2 prevents angiotensin II-induced connexin 40 and connexin 43 dysregulation by activating AMP kinase signaling in perfused beating rat atria.

Connexin-40 (Cx40) and Cx43 are the principal components of gap junctions. Dysregulation of connexin expression is clinically related to cardiac pathologies. 25-Hydroxy protopanaxadiol [25-OH-PPD, 20 (R)-dammarane-3β, 12β, 20, 25-tetrol], known as AD2, is a novel protopanaxadiol extracted from Panax ginseng that exhibits many pharmacological activities, but its effects on cardiac gap junctions are poorly understood.

Design, synthesis and evaluation of carbazole derivatives as potential antimicrobial agents.

Five series of novel carbazole derivatives containing an aminoguanidine, dihydrotriazine, thiosemicarbazide, semicarbazide or isonicotinic moiety were designed, synthesised and evaluated for their antimicrobial activities. Most of the compounds exhibited potent inhibitory activities towards different bacterial strains (including one multidrug-resistant clinical isolate) and one fungal strain with minimum inhibitory concentrations (MICs) between 0.5 and 16 µg/ml.

5-Aryl-furan derivatives bearing a phenylalanine- or isoleucine-derived rhodanine moiety as potential PTP1B inhibitors.

Two series of 5-aryl-furan derivatives bearing a phenylalanine- or isoleucine-derived rhodanine moiety were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, 5g was found to have the best PTP1B inhibitory potency (IC = 2.66 ± 0.

Synthesis and evaluation of HIF-1α inhibitory activities of novel panaxadiol derivatives.

Hypoxia-inducible factor 1α (HIF-1α) is a known regulator of tumor cell proliferation, migration, and angiogenesis. The presence of a high concentration of HIF-1α is positively correlated with the severity of cancer. Therefore, the inhibition of this pathway represents an important therapeutic target for the treatment of various types of cancer.

Arctigenin protects against depression by inhibiting microglial activation and neuroinflammation via HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB pathways.

Background And Purpose: Arctigenin, a major bioactive component of Fructus arctii, has been reported to have antidepressant-like effects. However, the mechanisms underlying these effects are still unclear. Neuroinflammation can be caused by excessive production of proinflammatory cytokines in microglia via high-mobility group box 1 (HMGB1)/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways, leading to depression.

Synthesis and evaluation of the HIF-1α inhibitory activity of 3(5)-substituted-4-(quinolin-4-yl)- and 4-(2-phenylpyridin-4-yl)pyrazoles as inhibitors of ALK5.

The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role in apoptosis, metastasis, and proliferation and is recognized as an important potential therapeutic target for cancer. Six series of 3(5)-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)pyrazoles (11a-d, 12a-d, and 18a-d) and 3(5)-(6-methylpyridin-2-yl)-4-(2-phenyl-pyridin-4-yl)pyrazoles (19a-d, 20a-d, and 21a-d) were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) and HIF-1α inhibitory activity at the enzyme and cell levels. The effect of the lead compound 20d (J-1012) on HIF-1α activation in HCT116 cells was investigated.

Acylation of 25-hydroxyprotopanaxatriol with aromatic acids increases cytotoxicity.

20(R)-25-hydroxyprotopanaxadiol (25-OH-PPD) is a natural compound showing a variety of anti-tumor effects. In an attempt to search for a new anti-cancer compound with higher antitumor activities, we designed and synthesized a series of 25-OH-PPD derivatives. Cytotoxicity assay of these derivatives towards MCF-7, A549, U87, HO-8901, Hela cancer cell lines and normal IOSE144 cell lines were tested by MTT assay.

Synthesis and biological evaluation of novel benzo[c][1,2,5]thiadiazol-5-yl and thieno[3,2-c]- pyridin-2-yl imidazole derivatives as ALK5 inhibitors.

Transforming growth factor (TGF-β), a key mediator of tumor growth and metastasis, has been recognized as an important cancer drug target. A series of benzo[c][1,2,5]thiadiazol-5-yl imidazoles (14a-g) and thieno[3,2-c]-pyridin-2-yl imidazoles (20a-g) were designed, synthesized, and evaluated for their activin receptor-like kinase 5 (ALK5) activities. Among these compounds, 14c showed the highest activity (IC = 0.

Design, synthesis, and antifibrosis evaluation of 4-(benzo-[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methyl- pyridin-2-yl)pyrazole and 3(5)-(6-methylpyridin- 2-yl)-4-(thieno-[3,2,-c]pyridin-2-yl)pyrazole derivatives.

Six series of 4-(benzo[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methylpyridin-2-yl)- pyrazoles 18a-d, 19a-d, 22a-d and 3(5)-(6-methylpyridin-2-yl)-4-(thieno[3,2,-c]- pyridin-2-yl)pyrazoles 20a-d, 21a-d, 23c, 23d have been synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) and p38α mitogen activated protein (MAP) kinase inhibitory activities in enzymatic assays. Among these compounds, the most active compound, 22c, inhibited ALK5 phosphorylation with an IC value of 0.030 μM in the enzymatic assay.

Synthesis and evaluation of the HIF-1α inhibitory activities of novel ursolic acid tetrazole derivatives.

The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of cancers. Here, we designed and synthesized 31 ursolic acid (UA) derivatives containing a tetrazole moiety and evaluated them for their potential anti-tumor activities as HIF-1α transcriptional inhibitors.

Synthesis and biological evaluation of tryptophan-derived rhodanine derivatives as PTP1B inhibitors and anti-bacterial agents.

Several series of novel tryptophan-derived rhodanine derivatives were synthesized and identified as potential competitive PTP1B inhibitors and antibacterial agents. Among the compounds studied, 10b was found to have the best in vitro inhibition activity against PTP1B (IC = 0.36 ± 0.

Discovery of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors.

Two series of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, IIIv was found to have the best in vitro inhibition activity against PTP1B (IC = 0.67 ± 0.